RA Meds May Lower Fertility

Action Points

The use of prednisone and nonsteroidal anti-inflammatory drugs may contribute to the subfertility common among women with rheumatoid arthritis.

Point out that other factors associated with a longer time to pregnanacy among the patients with RA were older age, nulliparous, and higher disease activity.

The use of prednisone and nonsteroidal anti-inflammatory drugs (NSAIDs) may contribute to the subfertility common among women with rheumatoid arthritis, Dutch researchers found.

In a multivariate analysis, preconception use of prednisone was associated with a 39% reduction in the likelihood of pregnancy (HR 0.61, 95% CI 0.45-0.83, P=0.002), according to Jenny Brouwer, a PhD candidate, and her colleagues at Erasmus Medical Center in Rotterdam.

And NSAID use preconception was associated with a 34% decreased chance of pregnancy (HR 0.66, 95% CI 0.46-0.94, P=0.022), the researchers reported online in Annals of the Rheumatic Diseases.

Retrospective studies and registries have demonstrated that women with rheumatoid arthritis typically have a harder time conceiving than healthy women.

However, "none of these studies have extensively examined the causes underlying the higher subfertility in rheumatoid arthritis, which may include disease activity, anti-rheumatic medication, and immunological factors," Brouwer and colleagues wrote.

To address this gap, they analyzed data from the prospective Netherlands on Pregnancy-induced Amelioration of Rheumatoid Arthritis (PARA) study, which included 245 women who were pregnant or attempting to conceive between May 2002 and August 2008.

Disease activity was considered high if the Disease Activity Score in 28 joints (DAS28) was above 5.1, intermediate if between 3.2 and 5.1, low if between 2.6 and 3.2, and remission if 2.6 or lower.

Other factors included in the analysis were age, parity, disease duration, smoking, positivity for rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPA), and treatment with prednisone, NSAIDs, sulfasalazine, or prior use of methotrexate.

Of the cohort, 84% became pregnant during the study period. It took longer than a year for 64 (31%) of them to conceive, and those 64 were classified with the 40 who failed to become pregnant as being subfertile, giving an overall rate of subfertility of 42%.

"This is much higher than the reported subfertility of 9% to 20% in the general population with a pregnancy wish in Western countries," the researchers noted.

A total of 67% of women considered to have high disease activity were in the subfertile category, as were 43% of those with intermediate disease activity, 37% of those with low activity, and 30% of those in remission.

The subfertile group were older, had higher DAS28 scores, more commonly were ACPA positive, and were more likely to use prednisone and NSAIDs.

Positivity for ACPA was more frequent among women who never conceived (80% versus 63%, P=0.05), as was RF positivity (90% versus 70%, P=0.01).

Along with use of NSAIDs and prednisone, these factors were significantly associated with a lower likelihood of pregnancy in the multivariate analysis:

Increasing age, HR 0.96 (95% CI 0.92-1, P=0.038)

Nulliparity, HR 0.52 (95% CI 0.38-0.70, P<0.001)

Higher DAS28, HR 0.81 (95% CI 0.71-0.93, P=0.002)

The effects of prednisone were examined further according to dosage. Among women on low doses of 7.5 mg or less per day, 43% were subfertile, as were 66% of those on higher doses and 36% of those not using prednisone.

The use of prednisone in doses above 7.5 mg per day also was associated with a significantly longer time until pregnancy (HR 0.50, 95% CI 0.33-0.76, P=0.001).

"The impact of high RA disease activity on fertility could be mediated via inflammatory mediators, since many cytokines, chemokines, and growth factors play an important role in the preimplantation blastocyst-endometrial interactions," Brouwer and colleagues explained.

As to why NSAIDs could contribute to pregnancy difficulties, they explained that these drugs "may interfere with ovulation, implantation, and placentation through inhibition of prostaglandin synthesis." In addition, the effects of prednisone might relate to suppression of the hypothalamic-pituitary-ovary axis.

"Based upon our results, it should be recommended that rheumatoid arthritis patients trying to conceive should strive for low disease activity, thereby avoiding NSAIDs and daily dosages of prednisone exceeding 7.5 mg," they wrote.

They also emphasized that disease control is also important for birth outcomes, as higher levels of DAS28 have been linked with low birth weights and the need for cesarean section.

They recommended that patients likely to experience reproductive difficulties be referred to a gynecologist, because if time to pregnancy can be minimized, "this may prevent extended suboptimal treatment and consequently functional disability and progression of joint damage."

The study was funded by the Dutch Arthritis Association.

The authors disclosed no relevant financial relationships.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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